<div><h3>Background</h3><p>Insulin resistance (IR) is induced by chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. It is not known whether drugs that affect IR such as Pioglitazone and Prednisone also affect serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The primary aim was to assess whether Pioglitazone by improving IR and/or inflammation decreases HCV viral load independently of standard of care HCV treatment. A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population.</p> <h3>Methodology/Principal Findings</h3><p>We designed a two-arm, parallel Pilot Study of overweight, treatment naïve genotype 4 HCV-infected patients at a public referral Liver Clinic in Giza, Egypt. The subjects received Pioglitazone (30 mg/day for 14 days) or Prednisone (40 mg/day for 4 days) in a randomized fashion, but the two arms can be considered independent pilot studies. Only changes from baseline within each arm were assessed and no contrasts of the interventions were made, as this was not an aim of the study. Among 105 consecutive HCV genotype 4 patients, 39 were enrolled based on the optimal sample size and power analysis according to the CONSORT statement; 20 to the Pioglitazone group and 19 to the Prednisone group. Pioglitazone was effective in decreasing serum HCV RNA at day-14 (n = 10; difference of means = 205,618 IU/ml; 95% CI 26,600 to 384,600; <em>P</em><0.001). Although Prednisone did increase serum HCV RNA at day-4 (n = 10; change from baseline = −42,786 IU/ml; 95% CI −85,500 to −15,700; <em>P</em> = 0.049), the log<sub>10</sub> HCV RNA titers were statistically not different from baseline day-0.</p> <h3>Conclusion/Significance</h3><p>This is the first documentation that Pioglitazone decreases the serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The novel findings of our Study provide the foundation for basic and clinical investigations on the molecular mechanisms responsible for the Pioglitazone-induced decrease in HCV genotype 4 RNA titers.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT01157975">NCT01157975</a></p> </div>